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Development of selective non-peptide angiotensin II type 2 receptor agonsists
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2010 (English)In: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 11, no 1, p. 57-66Article in journal (Refereed) Published
Abstract [en]

The development of the first drug-like selective angiotensin II type 2 (AT(2)) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT(1)) receptor/AT(2) receptor agonist L-162,313 is presented. Compound 22 with a K-i value of 0.4 nM for the AT(2) receptor and a K-i > 10 mu M for the AT(1) receptor induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhancesin vivo duodenal alkaline secretion in Sprague-Dawley rats and lowers the mean arterial blood pressure in anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. In addition, Compound 22 has a bioavailability of 20-30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT(2) receptor in more detail.

Place, publisher, year, edition, pages
2010. Vol. 11, no 1, p. 57-66
Keyword [en]
angiotensin, AT(2) receptor, AT(2) receptor agonist, drug development, medical chemistry
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-135602DOI: 10.1177/1470320309347790ISI: 000280518300008PubMedID: 19880657OAI: oai:DiVA.org:uu-135602DiVA, id: diva2:375257
Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2018-01-12Bibliographically approved

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